Pharmaceutical compositions for the treatment of movement disorders

ABSTRACT

The invention provides a pharmaceutical composition, medical food, dietary supplement or micronutrient for the treatment of a movement disorder comprising an NMDAR agonist or partial agonist as active ingredient therein in combination with a pharmaceutically acceptable carrier.

[0001] The present invention relates to pharmaceutical compositions forthe treatment of movement disorders. More particularly, the presentinvention relates to the use of N-methyl-D-aspartate type glutamatereceptor (NMDAR) agonists (NMDAR agonists, also known as NMDA agonists)and partial agonists for the treatment of movement disorders such asParkinsons disease.

[0002] NMDAR are a type of receptor for the excitatory neurotransmitterglutamate. MDAR contain additional modulatory sites, including thefollowing: glycine binding site, polyamine binding site, redox site,Zinc (Zn) site, phosphorylation sites, post-synaptic membrane dockingsites and protein-protein interaction sites (e.g., Lynch and Guttman,2001). The glycine binding site is sensitive to monocarboxyllic aminoacids including the endogenous amino acids glycineD-serine andD-alanine. Glycine is synthesized via serine or threonine by serinehydroxymethyltransferase. Synaptic glycine concentrations are regulatedby type 1 (GLYT1) and type 2 (GLYT2) glycine transporters, as well as byother amino acid transporters belonging to Systems A, L, ASC, and N(Sershen et al., 1979). GLYT1 transport inhibitors, such asN[3-(4′-fluorophenyl )-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS),potentiate NMDAR activity in vivo, (Bergeron et al., 1989; Klitenick etal., 2001) suggesting a critical role for glycine transporters in NMDARregulation. Methylated glycine derivates (e.g., methylglycine,sarcosine) may serve as non-specific glycine transport inhibitorsD-serine and D-alanine are metabolized by D-amino acid oxidase (DAAO),which is localized particularly in hindbrain. Further, DAAO is regulatedby a novel protein termed G72, which may affect metabolic activity ofthe DAAO enzyme (Chumakov et al., 2002). Glycine, D-serine and D-alaninelevels in brain may be modulated by administering exogenous compound(i.e., glycine, D-serine or D-alanine), or naturally occurringprecursors to these compounds including but not limited to L-serine,L-phosphoserine, D-phosphoserine and threonine, or by modulation of thesynthetic enzymes serine hydroxymethyltransferase or serine racemase.D-Serine or D-alanine levels may also be increased by modulationinhibiting D-serine or D-alanine breakdown, for example, by antagonizingDAAO activity either directly or indirectly (e.g., via modulatoryproteins).

[0003] Parkinsons disease is neurological disorder characterized bymovement disturbances related to extrapyramidal system dysfunction. Keysymptoms of Parkinsons disease include tremor, rigidity, dystonia,bradykinesia and akinesia. The primary current treatments for Parkinsonsdisease include anticholinergics, L-dopa and MAO inhibitors. Dyskinesiais a long-term consequence of antiParkinsonian treatment. Parkinsonsdisease may occur under several conditions, including 1) idiopathically,2) as a result of exposure to environmental toxins, particularly thoseaffecting the dopamine system (e.g., 6-OH dopamine, MPTP) or 3) duringtreatment with antidopaminergic agents, particularly in connection withschizophrenia. Parkinsonian side effects are particularly common duringtreatment using typical antipsychotic agents such as, but not limitedto, haloperidol, flupenazine or chlorpromazine. More recently developedatypical antipsychotics such as olanzapine, risperidone, quetiapine,ziprasidone and aripiprazole are associated with decreased rates ofParkinsonian symptoms. Significant Parkinsonian symptoms also occurspontaneously in up to 20% of individuals with schizophrenia. Ingeneral, agents effective in treatment of drug-induced Parkinsoniansymptoms, such as anticholinergics and amantadine, are also effective intreatment of idiopathic Parkinsons disease. Symptoms of Parkinsonsdisease may be evaluated using the Simpson Angus Scale (SAS, Simpson &Angus, 1970) or similar instrument.

[0004] Dyskinesias are abnormal movements characterized by having asnakelike or writhing character. Dyskinesias may occur as a consequenceof neurological disease such as Huntington's chorea, as a result ofdamage to specific brain regions such as corpus striatum or subthalamicnucleus, or as a consequence of medical conditions (e.g., Syndenham'schorea), but may also occur as a consequence of long-term exposure toantipsychotic medication. Tardive dyskinesia (TD) is a form ofdyskinesia that results from long-term exposure to antipsychotics suchas chlorpromazine or haloperidol. TD occurs less frequently followingtreatment with newer antipsychotics, and symptoms of TD can besuppressed by clozapine. Symptoms of TD are evaluated using instrumentssuch as the Abnormal Involuntary Movement Scale (AIMS, Guy, 1976).

[0005] Tics are sudden, rapid, recurrent, nonrhythmic stereotypedmovements or vocalizations. Examples of tic disorders include Tourette'sdisorder, Chronic Motor or Vocal Tic Disorder, Transient Tic Disorderand Tic Disoder Not Otherwise Specified. Tourette's disorder isinherited in an autosomal dominant fashion, which penetrance ofapproximately 70% in females and 99% in males (DSM-IV, 1994, p. 100).Obsessive compulsive disorder is a disorder characterized by recurrentobsessions or compulsions, leading often to repetitive motor behaviors(e.g., hand washing, ordering, checking) or mental acts (e.g., praying,counting, repeating words silently) (DSM-IV, 1994, p. 418).Obsessive-compulsive disorder is common in patients with Tourette'sdisorder. Conversely, 20-30% of individuals with Obsessive-Compulsivedisorder have reported current or past tics. Etiology of tic disordersand obsessive compulsive disorder are unknown, but may involveautoimmune factors (Hallet et al., 2000), serotonergic dysfunction(e.g., Dursun et al., 1996), or gene expression abnormalities (Greer etal., 2002). Nevertheless, NMDAR may play a critical role in regulationof circuits involved in movement disorders, as NMDAR antagonists worsensymptoms in animal models of the disorder (McGrath et al., 2000).

[0006] Although the primary pathology in Parkinsons disease is a loss ofdopaminergic neurons in the substantia nigra and ventral tegmentalareas, expression of symptoms is the result of interactions betweenmultiple populations of dopaminergic, glutamatergic and GABAergicneurons within the extrapyramidal system. Many neurons involved in thepathophysiology of Parkinsons disease express additional transmitters,including enkephalin (ENK), substance P (SP), somatostatin (SOM),opioids, adenosine, and acetylcholine (ACh). Key structures that may beinvolved in Parkinsons disease include the nigrostiatal, mesolimbic andmesocortical dopaminegic systems, the basal ganglia including corpusstriatum, caudate, putamen and globus pallidus, the subthalamic nuclei,cerebral cortex, cerebellum and portions of thalamus.

[0007] NMDAR play a key role in the regulation of movement and striatalfunction. NMDARs are found on multiple classes of neuron within striatumincluding projection neurons and internuerons. NMDARs are composed ofmultiple subunits including an NR1 subunit which is present in virtuallyall functional NMDARs, and NR2 subunits that are present in variableproporations. Four NR2 subunits (NR2A-D) have been described. NR2Aexpression is high in GABAergic neurons that express the marker GAD67,intermediate over SP neurons, low in ENK neurons, not found incholinergic and SOM neurons. In contrast, NR2B expression is intense inall populations of neurons, while expression of NR2C,D is weak(Kuppenbender et al., 2000). The existence of multiple subforms of NMDARin striatum is supported by the observation that NMDARs controlling GABAand DA release are less sensitive to NMDA than receptors controllingspermidine or ACh release (Nankai et al., 1995).

[0008] Current theories of Parkinsons disease postulate an importantrole of NMDAR in the networks subserving development of Parkinsoniansymptoms. However, based upon the clinical observation that amantadine,a widely used anti-Parkinsonian agent, has NMDAR antagonist (as opposedto agonist) properties, it has been suggested that NMDAR antagonists maybe beneficial in treating movement disorders. Other findings, such asthe ability of glycine antagonists to increase locomotion inmonoamine-depleted mice (Slusher et al., 1994) have also been used toteach use of NMDAR antagonists in the treatment oParkinsons disease.Thus e.g. the literature is replete with references such as U.S. Pat.No. 6,284,774 which teach the use of NMDA receptor antagonists for thetreatment of Parkinsons disease.

[0009] In contradistinction to the teachings of the prior art it has nowbeen surprisingly found that NMDA receptor agonists, particularly thosethat target the NMDAR-associated glycine binding site are effective forthe treatment of movement disorders such as Parkinsons disease.

[0010] NMDAR agonists described in the present application, includingglycine and D-serine, are naturally occurring compounds that may bemarketed as pharmaceuticals, medical foods or dietary supplements.Previous applications (e.g., U.S. Pat. No. 6,228,875) have described andclaimed use of NMDAR agonists only as pharmaceuticals. In contrast, thepresent application teaches use as medical foods or dietary supplementsas well as pharmaceuticals. Thus according to the present inventionthere is now provided a pharmaceutical composition, medical food ordietary supplement for the treatment of a movement disorder comprisingan NMDAR agonist or partial agonist as active ingredient therein incombination with a pharmaceutically acceptable carrier.

[0011] The present invention also provides for the use of an NMDARagonist or partial agonist in the manufacture of a pharmaceuticalcomposition, medical food, or dietary supplement for the treatment of amovement disorder and especially for the treatment ofantipsychotic-induced movement disorders and Parkinsons disease.

[0012] Prior literature regarding use of NMDAR agonists (as opposed toantagonists) in treatment of Parkinsons disease is minimal. Casey andShiigi (1999) showed that administration of ketamine inducesbradykinesia, dystonia and salivation in neuroleptic sensitized monkeys(Shiigi and Casey, 1999), suggesting that NMDA dysfunction mightcontribute to symptoms. Schneider et al. (Brain Res 860:190-4, 1991)demonstrated that low dose (320 or 1000 mg/kg) D-cycloserinesignificantly improved variable delayed-response task (VDR) performancein MPTP-treated monkeys but did not show improvement in bradykinesia,tremor or other core Parkinsonian symptoms (Schneider et al., Brain Res860:190-4, 1991).

[0013] In U.S. Pat. No. 6,228,875 there is described and claimed methodsand pharmaceutical compositions for treating neuropsychiatric disorderssuch as schizophrenia, Alzheimer's Disease, autism, depression, benignforgetfulness, childhood learning disorders, close head injury, andattention deficit disorder using at least one agonist of the glycinesite of an NMDA receptor however said patent neither teaches norsuggests that such agonists are effective for the treatment of movementdisorders such as Parkinsons disease.

[0014] The present findings are also not anticipated by subsequentarticles relating to the examples in Tsai and Coyle '875. As shown inTable 2 of Tsai et al., 1998, a paper relating to '875, patientsparticipating in studies disclosed in '875 had minimal levels ofpretreatment Parkinsonian symptoms as measured by the SAS (1.4±1.4points) and dyskinetic symptoms as measured by the AIMS (0.3±0.7points). Because of patients recruited for that study, therefore, Tsaiand Coyle were unable to assess effects of NMDA agonists on movementdisorders in general or on Parkinsonian and dyskinetic symptoms inparticular. A subsequent study (Tsai et al., 1999) also did not findsignificant change in SAS or AIMS scores during treatment with D-serinecombined with clozapine. In Tsai and Coyle '875, data are presented alsowith D-alanine and N-methylglycine. In these cases also, no significantchanges in SAS or AIMS scores were observed, due in part to lowbaseline. levels. Therefore, neither Tsai and Coyle '875 nor relatedreferences teach use of NMDA agonists or partial agonists in treatmentof movement disorders or movement-related side effects of antipsychoticmedication. In a prior study of glycine (Heresco-Levy et al., 1999,Table 3), SAS scores declined from 1.3 to 0.6 points during glycinetreatment vs. no change during placebo. AIMS scores declined from 1.9 to1.4 during glycine but increased during placebo. Nevertheless, in thatstudy, change scores for SAS and AIMS were not significant for glycinevs. placebo (p>0.02 for both). Thus, the present results are notanticipated by '875 or continuations thereof.

[0015] In prior studies of schizophrenia, we and others havedemonstrated improvement in negative symptoms during treatment with theNMDAR agonists glycine (Heresco-Levy et al., 1999a; Javitt et al., 2000;Heresco-Levy et al., submitted), D-serine (Tsai et al., 1999) andD-cycloserine (Heresco-Levy et al., 1998; Goff et al., 1999;Heresco-Levy et al., 1999b). Several negative symptoms, including motorretardation and affective blunting resemble symptoms of Parkinsonsdisease. Nevertheless, these studies did not show significantimprovement of motor symptoms during treatment with NMDAR agonists orthe partial agonist D-cycloserine, and did not teach use of NMDARagonists in treatment of movement disorders.

[0016] The mechanism by which NMDAR agonists or partial agonistsameliorate symptoms of movement disorder remain to be determined. Onepotential explanation, however, is that subpopulations of NMDAR maycontribute differentially to both pathogenesis and therapeutics. Thus,in terms of pathogenesis, NR2B receptors in striatum have beenspecifically implicated (Nash & Brotchie, 2002). Further, agents thathave shown greatest preliminary effectiveness in Parkinsons disease areall NR2B antagonists (Nikam & Meltzer, 2002). In monkeys, NR2A and NR2Bselective antagonists were observed to have differential effects, withthe NR2A antagonist MDL 100,453 worsening symptoms of dyskinesia(Woodward et al., 1999). NR2B receptors have numerically lower affinityfor glycine than NR2A receptors, and so may be saturated underphysiological conditions. Administration of NMDAR agonists such asglycine and D-serine and the NMDA partial agonist D-cycloserine maytherefore selectively active NR2A receptors. Activation of NR2A vs. NR2Breceptors by NMDAR agonists and partial agonists may, therefore, restorethe balance between NR2A and NR2B containing receptors similarly andadditively to the effects of NR2B antagonists.

[0017] The finding that NMDAR agonists improve antipsychotic-inducedmovement disorders including Parkinsoriism and TD is not anticipated byprior literature. These findings moreover indicate that NMDAR agonistsmay be effective in treatment of other movement disorders, includingParkinsons disease, dyskinetic disorders, obsessive-compulsive disorder,tic disorders etc.

[0018] While the invention will now be described in connection. withcertain preferred embodiments in the following examples so that aspectsthereof may be more fully understood and appreciated, it is not intendedto limit the invention to these particular embodiments. On the contrary,it is intended to cover all alternatives, modifications and equivalentsas may be included within the scope of the invention as defined by theappended claims. Thus, the following examples which include preferredembodiments will serve to illustrate the practice of this invention, itbeing understood that the particulars shown are by way of example andfor purposes of illustrative discussion of preferred embodiments of thepresent invention only and are presented in the cause of providing whatis believed to be the most useful and readily understood description offormulation procedures as well as of the principles and conceptualaspects of the invention.

EXAMPLE 1 Beneficial Effects of High Dose Glycine (60 g/d) on EPS and TDin Schizophrenia

[0019] Methods:

[0020] The study was approved by the appropriate institutional reviewboards. Seventeen stable inpatients meeting DSM-IV criteria forschizophrenia and free of other axis I diagnoses or significant medicalillness were. enrolled in the study. Diagnosis was established on thebasis of semistructured psychiatric interviews, review of all availablemedical records, and confirmation by two board-certified psychiatrists.Patients fulfilled criteria for treatment resistance used in previoustrials of glycine and had been receiving stable doses of olanzapine orrisperidone for at least 3 months before study entry. Medication dosesremained fixed throughout the study.

[0021] After complete description of the study, written informed consentwas obtained from all participating patients. The double-blind,placebo-controlled, crossover study consisted of two random-order 6-weektreatment arms (glycine 0.8 g/kg/day, or placebo), separated by a 2-weekadjuvant treatment washout. Patients were assessed biweekly with thePositive and Negative Syndrome Scale (PANSS), Brief Psychiatric RatingScale (BPRS), Simpson-Angus Rating Scale (SAS), and Abnormal InvoluntaryMovement Scale (AIMS) performed by one trained research psychiatrist, aspreviously described (3). CBC and SMA-20 measures were assessed biweeklythroughout the study. Trough glycine and serine serum levels wereassessed at baseline and at the end of the two treatment phases. Datawere analyzed by repeated measures ANOVA with within group factor ofstudy phase (glycine/placebo) and time within study phase (pre/post),and between group factor of treatment order.

[0022] Results

[0023] Three patients were withdrawn from the study during glycineadministration due to non-compliance and mild upper gastrointestinaltract discomfort that ceased following discontinuation of glycinetreatment (2 patients). Three of the 14 patients who completed the studywere women and 11 were men. Their mean age was 46.5 years (SD=9.6), themean duration of their illness was 25.8 years (SD=11.0) and the meanduration of their current hospitalization was 3.0 years (SD=3.7). Tenpatients were receiving olanzapine (mean daily dose: 14.3 mg (SD=3.1);four patients were receiving risperidone (mean daily dose: 6.2 mg(SD=3.1). Seven patients were randomized to receive placebo during thefirst treatment phase, eight received glycine. Repeated measuresmultivariate analyses of variance were performed with within-subjectfactors of treatment phase (placebo versus glycine) and time withinphase (baseline versus week 6) and a between-subjects factor oftreatment order.

[0024] Analyses demonstrated highly significant, large effect sizereductions in PANSS negative and cognitive symptoms and for BPRS totalscores (Table 1), indicating significant therapeutic efficacy ofglycine. Smaller but still significant improvements were observed forpositive symptoms. Treatment effects for negative symptoms remainedhighly significant (F=22.2, df=1,8, p<0.002) even following covariationfor changes in all other PANSS symptom factors.

[0025] Significant moderate-effect-size treatment effects were noted forboth SAS and AIMS scores that decreased following glycine treatment(Table 1). SAS scores decreased by 1.3 points (18%) during glycinetreatment vs. a 0.5 point increase during placebo treatment, the resultbeing statistically significant (p<0.05). AIMS scores decreased by 1.0point (32.2.%) during glycine treatment vs. an 0.3 point increase duringplacebo treatment, the results being statistically significant (p<0.02).This represents the first study to show changes in SAS or AIMS scoreduring treatment with NMDAR agonists. TABLE 1 Mean (sd) PANSS, BPRS, SASand AIMS Scores of 14 Inpatients with Treatment-Resistant SchizophreniaDuring the Addition of Glycine, 0.8 g/kg/day, and Placebo to Olanzapineand Risperidone Treatment¹ % Change Adjuvant Score at Score at ANOVAduring Effect Treatment Baseline Week 6 (F, p) glycine² size (d) PANSSNegative Glycine 24.6 (4.4) 20.4 (3.9) 72.1, 23.3 (8.4) 2.1 SymptomsPlacebo 22.0 (3.9) 23.3 (4.0) 0.006 CI: 18-28% Positive Glycine 15.4(2.2) 14.0 (1.5) 7.3, 11.4 (11.7) 0.7 Symptoms Placebo 14.3 (1.1) 14.7(1.9) 0.02 CI: 5-18% , Cognitive Glycine 19.1 (2.8) 17.9 (3.1) 11.0, 9.2 (6.8) 0.9 Symptoms Placebo 18.0 (3.4) 18.6 (2.4) 0.006 CI: 5-132%Excitement Glycine 13.2 (2.1) 12.0 (1.5) 13.3, 10.6 (20.9) 0.6 Placebo12.3 (1.6) 12.9 (2.1) 0.003 CI: −2-23 Depression Glycine 14.4 (3.0) 13.4(2.1) 7.2,  7.4 (17.1) 0.7 Placebo 13.3 (2.3) 14.4 (3.0) 0.02 CI: −2-17BPRS Total Glycine 42.6 (6.0) 36.6 (4.8) 35.0, 13.7 (7.5) 1.6 Placebo37.9 (4.6) 40.4 (6.4) 0.0001 CI: 9-18 SAS Glycine  5.3 (3.3)  4.0 (3.0)4.7, 17.9 (40.1) 0.6 Placebo  4.4 (2.7)  4.9 (3.3) 0.05 CI: −5-41 AIMSGlycine  3.6 (2.0)  2.6 (7.1) 7.5, 32.2 (30.4) 0.6 Placebo  2.9 (1.6) 3.2 (2.4) 0.02 CI: 15-50

EXAMPLE 2 Beneficial Effects of High Dose D-serine (0.03 g/d) on EPS andTD in Schizophrenia

[0026] Methods: Methods for this study are the same as in example 1,except that D-serine (0.3 g/d=approx. 2.1 g/day) was used for treatment.As previously, outcome was assessd using the PANSS, SAS and AIMS. Inaddition, the Schedule for Assessement of Negative Symptoms (SANS) wasused to provide further assessment of negative symptoms. This representsan interim analysis of an ongoing study. Data were analyzed bybetween-treatment t-test of change scores during D-serine or placebotreatment. Data are analyzed only from subjects (n=23) who completedboth study phases.

[0027] Results: As with glycine, D-serine led to highly significantimprovements in negative, positive and cognitive symptoms. ofschizophrenia, similar to reported previously by Tsai et al. (1998). Asrated by the SAS, a highly significant 42% decline in Parkinsoniansymptoms was observed during D-serine, but not placebo, treatment,leading to a highly significant between group response difference (seeTable 2). As rated by the AIMS, a highly significant 50% decline indyskinetic symptoms was observed during D-serine, but not placebo,treatment, leading to a highly significant between group responsedifference (see Table 2). These findings are similar to those observedpreviously with glycine, as detailed in example 1. TABLE 2 Mean (sd)Positive and Negative Syndrome (PANSS), Simpson Angus (SAS) and AbnormalInvoluntary Movement (AIMS) scale scores during D-serine (n = 23) andplacebo (n = 22) treatment (crossover design) Treatment Treatment week ΔBetween-group Assignment 0 6 symptoms difference (t, p) PANSS PositiveD-serine 14.2 ± 2.3 13.0 ± 2.3 −1.2 ± 1.1 t = 2.90, Symptoms Placebo13.7 ± 2.4 13.5 ± 2.3 −0.3 ± 1.2 p = .006 Negative D-serine 23.9 ± 4.021.0 ± 3.5 −2.9 ± 1.9 t = 4.53, symptoms Placebo 22.8 ± 3.5 22.5 ± 3.0−0.3 ± 1.8 p < .00001 Cognitive D-serine 18.5 ± 2.2 17.1 ± 2.7 −1.4 ±1.3 t = 5.90 symptoms Placebo 18.0 ± 2.5 18.4 ± 2.1   0.4 ± 1.1 p <0.0001 Depression D-serine 15.3 ± 2.6 13.8 ± 2.2 −1.5 ± 1.8 t = 4.85,Placebo 14.5 ± 2.6 15.1 ± 2.4   0.6 ± 1.5 p < .00001 Excitement D-serine11.6 ± 1.5 10.9 ± 1.4 −0.7 ± 1.2 t = 1.21, Placebo 11.1 ± 1.6 11.0 ± 1.5−0.1 ± 1.2 p = .2 SANS Total D-serine 60.0 ± 9.3 51.9 ± 8.0  −9.0 ± 54.3t = 7.15 (with globals) Placebo  56.1 ± 10.1 56.9 ± 9.4   0.9 ± 5.3 p <.00001 SAS D-serine  4.2 ± 1.4  2.4 ± 0.8 −1.8 + 1.3 t = 5.66, Placebo 3.7 ± 1.6  4.0 ± 1.3   0.2 ± 1.1 p < 00001 AIMS D-serine  3.0 ± 0.8 1.6 ± 1.2 −1.4 ± 1.1 t = 5.51 Placebo  2.5 ± 1.2  2.7 ± 0.9   0.2 ± 0.9p < .00001

EXAMPLE 3 Beneficial Effects of the Partial Agonist D-cycloserine

[0028] Methods: Methods for this study are the same as in example 1,except that D-cycloserine (50 mg/d) was used for treatment. Aspreviously, outcome was assessd using the PANSS, SAS and AIMS. Inaddition, the Schedule for Assessement of Negative Symptoms (SANS) wasused to provide further assessment of negative symptoms. Data are pooledfrom two previously published studies (Heresco-Levy et al., 1998, 2002).Because analyses were confirmatory, one-tailed statistics were usedthroughout.

[0029] Results: Significant improvements in positive and negativesymptoms and general psychopathology were observed, as previouslydescribed. D-cycloserine treatment was associated with a significantreduction in dyskinetic symptoms (t=2.21, p<0.025, one tailed) and anearly significant improvement in Parkinsonian symptoms (t=1.77, p.=04,one tailed) (Table 3). TABLE 3 Mean (sd) Positive and Negative Syndrome(PANSS), Simpson Angus (SAS) and Abnormal Involuntary Movement (AIMS)scale scores during D-cycloserine (n = 26) and placebo (n = 28)treatment (crossover design) Between- group Treatment Week WithinTreatment Ä difference Assignment Phase symptoms (t, p) PANSS 0 6Positive D-cycloserine 26.7 ± 4.5 24.6 ± 4.1 −2.1 ± 2.6 t = 3.01,symptoms p < .003 Placebo 25.8 ± 3.7   26 ± 4.2   0.1 ± 2.8 NegativeD-cycloserine 34.6 ± 6.2 31.4 ± 6.5 −3.2 ± 2.5 t = 2.93, symptoms p <.003 Placebo 33.9 ± 6.9 32.6 ± 6.4 −1.2 ± 2.4 General D-cycloserine 58.7± 8.4 53.8 ± 8.2 −4.9 ± 6.2 t = 2.70, Psycho- p < .005 pathaol- ogyPlacebo 57.5 ± 8.2 57.1 ± 9.5 −0.4 ± 6.2 Total D-cycloserine   120 ±16.7 109.7 ± 15.8 −10.2 ± 8.9  t = 3.60, Symptoms p < .001 Placebo 117.2± 16.2 115.6 ± 17.4 −1.6 ± 8.8 SAS D-cycloserine  4.3 ± 2.4  3.6 ± 2.1−0.7 ± 1.7 t = 1.77 Placebo  3.6 ± 2.1  3.8 ± 2.2   0.2 ± 1.9 p < .05AIMS D-cycloserine  4.7 ± 3.1 3.9 ± 3  −0.8 ± 1.3 t = 2.21 Placebo  3.9± 2.7  3.9 ± 2.6    0 ± 1.2 p < .03

EXAMPLE 4 Effect of Glycine on Vacuous Chewing Motions in Rodents

[0030] Vacuous chewing movements (VCM) are a rodent model of TD(Andreassen et al., 1996). In this model, animals are treatedchronically with antipsychotics and their vacuous chewing motions areassessed by observation. This model has been shown to be sensitive todifferential effects of typical and atypical antipsychotics andpotential anti-dyskinetic agents. This example describes effects of theNMDAR agonist glycine on haloperidol-induced VCM.

[0031] Methods and Materials

[0032] Subjects

[0033] Sprague-Dewley rats (Harlan Laboratories, Jerusalem, Israel)weighing 150 to 170 g. were used. The rats were housed in polycarbonatecages (4 in each cage), maintained under a 12 hour-12 hour dark-light(04.00-16.00 hours) cycle, and were allowed water ad libitum. In orderto limit neuroleptic-induced weight gain, the food was restricted to 15g. pellets per animal per day, as used by Andreassen et al (1996). Ratswere weighed biweekly throughout the study. Room temperature wasmaintained at 22±2° C. All procedures were conducted in accordance withlocal and international laws for the care and use of laboratory animals.

[0034] Protocol and Drugs

[0035] For two weeks prior to the first drug injection, animals werehandled daily and habituated to the animal colony and the proceduresrelated to drug administration and video recording situation.Subsequently (week 0), rats underwent a behavior video recording sessionfollowing which they were randomized to a haloperidol treatment and acontrol group. The rats in the treatment group received an intramuscularinjection in the thigh muscles with haloperidol decanoate (Pericate,Unipharm Ltd., Tel Aviv, Israel), 100 mg/ml in sesame oil, at a dose of0.35 mg/kg. The control rats were similarly injected with an equalvolume of phosphate buffered saline (PBS). Twenty-three G hypodermicneedles were used for all injections. Subsequently, the haloperidoldecanoate and saline injections were repeated every four weeks, for 20weeks. Additional behavior video recording sessions were performed atweeks 12, 20 and 24 (i.e., 4 weeks after the last (fifth) injection).During the injection procedures, rats were handheld with minimalrestraint.

[0036] On the basis of the results of the behavior assessment performed24 weeks after the first haloperidol injection (i.e., baseline day), thehaloperidol-treated rats were assigned to 10 subject-each treatmentgroups having an equal mean frequency of observed VCM episodes. One weeklater (i.e., test day), the groups reported on here were randomized toreceive one intraperitoneal injection with either 0.5 ml PBS (vehicle)or 1.6 g/kg glycine in 0.5 ml PBS. Rats underwent a video recordedbehavior assessment session 30-150 minutes following the injection. Twoweeks after the test day (i.e., post-test day), the video recordedbehavior assessment session was repeated in order to investigatelonger-term effects of the experimental treatments.

[0037] Behavioral Observations and Statistics

[0038] Before experiments were started, the rats were handled andhabituated to the behavior observation situation. During videotaping,the rats were kept in a clear perspex cage (13×20.5×13.5 cm), equippedwith mirrors allowing videotaping of the rat from all sidessimultaneously. The behavior of the animals was videotaped for 5 minutesafter a 1 minute adaptation period in the cage.

[0039] A trained observer, unaware of the treatment received by therats, scored the behavior while watching the videotapes. A VCM episodewas defined as a bout of vertical deflections of the lower jaw, whichcould be accompanied by contractions of the jaw musculature. Statisticalanalyses were performed using the STATISTICA software package (StatSoftInc., USA). Student's t-test was used to assess the effects of chronichaloperidol treatment compared to placebo. Analysis of variance (ANOVA)with one between group factor (experimental drug treatment) and onerepeated measures factor (baseline day vs. test day vs. post-treatmentday) was performed to assess the effects of glycine. The statisticalsignificance of interaction of the between group factor and the repeatedmeasures factor is determined in the STATISTICA software package usingthe Rao R statistic and the F distribution. Post hoc Newman-Keuls testswere used for comparisons between treatments.

[0040] RESULTS

[0041] Effects of chronic haloperidol treatment on motor activity Ratsthat had received haloperidol for 24 weeks displayed an approximately4-fold significantly higher number of VCM episodes than rats that hadreceived placebo (t=3.29, df=47, p<0.001) indicating that chronichaloperidol administration induced spontaneous VCM. Furthermore, thenumber of rearing episodes was significantly lower in thehaloperidol-treated group (t=5.2, df=47, p<0.0001). Moreover, mobilityin general was significantly reduced in the haloperidol-treated rats.During a 5 minute observation interval, the mean time spend inimmobility by the haloperidol-treated rats was 103.2±7.8 seconds, incontrast to 53.0±12.7 seconds spent in immobility by the rats that hadreceived placebo (t=2.9, df=45, p<0.005). Overall, the number ofgrooming episodes did not differ between haloperidol-treated rats andcontrols (t=1.4, df=47, p<0.17).

[0042] VCM measures were compared on test day between animals receivingvehicle injections and those receiving glycine. One way ANOVA withrepeated measures revealed significant interaction of drug andobservation day on VCM frequency with Rao R (6,64)=3.44, p<0.005). Posthoc comparisons of VCM frequency at baseline and following GLYadministration at the test day further revealed that the administrationof GLY resulted in a significant 82% reduction in the number of VCMepisodes (p<0.001). Moreover, post hoc comparison of VCM frequencies inthe placebo and glycine groups at test day indicated a significantlylower VCM frequency following glycine acute administration (p<0.01). Thenumber of VCM in the glycine-treated groups at baseline and post-testday did not differ significantly (p<0.07), indicating that 2 weekspost-acute GLY administration, VCM levels returned to their previous,pre-experimental treatment levels. These findings, overall, support theclinical observation of decreased VCM following NMDAR agonist treatment.

[0043] The examples above demonstrate effectiveness of two full NMDARagonists, as well as a partial NMDAR agonist in treatment ofantipsychotic-induced movement disorder, including Parkinsonian anddyskinetic symptoms. Other methods for augmenting NMDA transmission viathe glycine binding site have been proposed including use of glycinetransport inhibitors (aka transport antagonists, uptake inhibitors,uptake antagonists), acting at the GLYT1, GLYT2, System A, System ASC orother glycine transport sites, and modulators of D-serine metabolismincluding inhibitor of b-serine transport and of D-amino acid oxidase.Agents may be screened for effectiveness in stimulating NMDAtransmission in vitro using assays, for example, measuring modulation ofNMDAR-mediatedactivity in hippocampal slices (Bergeron et al., 1998) orof NMDAR-stimulated dopamine release in isolated mouse striatum (Javittet al., 2000). Agents may be screened in vivo using assays, for example,measuring amphetamine induced dopamine release or NMDAR-mediatedelectrophysiological activity (Klitenick et al., 2001). Agents will beeffective in ameliorating movement disorders at doses sufficient topotentiate NMDAR-mediated neurotransmission in vivo.

[0044] In addition to the embodiments listed above, prodrugs may also beadministered. Prodrugs are defined as agents that are not themselvesagonists of the NMDAR, but which enter the brain and are converted ormetabolized there into effective agonists. An example of a glycineprodrug is milacemide (Doheny et al., 1996). Simple precursors can bemade by esterification, alkylation or other linkage (Kao et al., 2000;Schwartz et al., 1991; Toth et al., 1986), most effectively tohydrophobic groups that increase lipophilicity and diffusion into CNS(e.g., Cooper et al., 1987). In a preferred embodiment of the invention,NMDAR agonists, including but not limited to glycine, D-serine, orD-alanine, are conjugated to molecules that are actively transportedinto the CNS, leading to increased central penetration (e.g., Battagliaet al., 2000; Fernandez et al., 2000; Bonina et al., 1999; Halmos etal., 1997; de Boer et al., 2002; Kido e tal., 2001, Fisher et al., 2002,Rouselle et al., 2002). Precursors to glycine, D-serine or D-alanine,including threonine, L-phosphoserine and D-phosphoserine, may also beincorporated into prodrugs.

[0045] The pharmaceutical compositions can be administered to thepatient by any, or a combination, of several routes, such as oral,intravenous, trans-mucosal (e.g., nasal, vaginal, etc.), pulmonary,transdermal, ocular, buccal, sublingual, intraperitoneal, intrathecal,intramuscular, or long term depot preparation. Solid compositions fororal administration can contain suitable carriers or excipients, such ascorn starch, gelatin, lactose, acacia, sucrose, microcrystallinecellulose, kaolin, mannitol, dicalcium phosphate, calcium carbonate,sodium chloride, lipids, alginic acid, or ingredients for controlledslow release. Disintegrators that can be used include, withoutlimitation, micro-crystalline cellulose, corn starch, sodium starchglycolate and alginic acid. Tablet binders that may be used include,without limitation, acacia, methylcellulose, sodiumcarboxymethylcellulose, polyvinylpyrrolidone (Povidone), hydroxypropylmethylcellulose, sucrose, starch, and ethylcellulose.

[0046] Liquid compositions for oral administration prepared in water orother aqueous vehicles can include solutions, emulsions, syrups, andelixirs containing, together with the active compound(s), wettingagents, sweeteners, coloring agents, and flavoring agents. Variousliquid and powder compositions can be prepared by conventional methodsfor inhalation into the lungs of the patient to be treated.

[0047] Injectable compositions may contain various carriers such asvegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate,ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol,propylene glycol, liquid polyethylene glycol, and the like). Forintravenous injections, the compounds may be administered by the dripmethod, whereby a pharmaceutical composition containing the activecompound(s) and a physiologically acceptable excipient is infused.Physiologically acceptable excipients may include, for example, 5%dextrose, 0.9% saline, Ringer's solution or other suitable excipients.For intramuscular preparations, a sterile composition of a suitablesoluble salt form of the compound can be dissolved and administered in apharmaceutical excipient such as Water-for-Injection, 0.9% saline, or 5%glucose solution, or depot forms of the compounds (e.g., decanoate,palmitate, undecylenic, enanthate) can be dissolved in sesame oil.Alternatively, the pharmaceutical composition can be formulated as achewing gum, lollipop, or the like.

[0048] It will be evident to those skilled in the art that the inventionis not limited to the details of the foregoing illustrative examples andthat the present invention may be embodied in other specific formswithout departing from the essential attributes thereof, and it istherefore desired that the present embodiments and examples beconsidered in all respects as illustrative and not restrictive,reference being made to the appended claims, rather than to theforegoing description, and all changes which come within the meaning andrange of equivalency of the claims are therefore intended to be embracedtherein.

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What is claimed is:
 1. A pharmaceutical composition, medical food,dietary supplement or micronutrient for the treatment of a movementdisorder comprising an NMDAR agonist or partial agonist as activeingredient therein in combination with a pharmaceutically acceptablecarrier.
 2. A pharmaceutical composition according to claim 1 whereinsaid movement disorder is Parkinsons disease.
 3. A pharmaceuticalcomposition, medical food, dietary supplement or micronutrient accordingto claim 1 wherein the glycine-site agonists are selected from the groupconsisting of glycine and D-serine.
 4. A pharmaceutical composition,medical food, dietary supplement or micronutrient according to claim 1wherein the glycine-site agonists are selected from the group consistingof precursors to glycine, D-serine and D-cycloserine.
 5. Use of NMDARagonists and partial agonists for the manufacture of a pharmaceuticalcomposition, medical food, dietary supplement or micronutrient for thetreatment of movement disorders.
 6. A method for the treatment of amovement disorder comprising administering to a patient a atherapeutically effective amount, for alleviating motor disordersymptoms, of an agonist or partial agonist of the glycine-site of anNMDA receptor.
 7. The method of claim 6 in which NMDAR agonists andpartial agonists are administered at a dose sufficient to augment NMDARmediated neurotransmission.
 8. The method of claim 6 in which NMDARagonists target the glutamate binding site of the NMDAR complex.
 9. Themethod of claim 6 in which NMDAR agonists target the polyamine bindingsite of the NMDA complex. 10 The method of claim 6 in which NMDARagonists target the glycine binding site of the NMDAR complex.
 11. Themethod of claim 6 in which the glycine-site agonists are selected from agroup that includes glycine or d-serine.
 12. The method of claim 6 inwhich agents are used that are precursors to glycine, d-serine ord-cycloserine.
 13. The method of claim 6 in which partial agonists ofthe NMDA-associated glycine binding site are used in place ofglycine-site full agonists.
 14. The method of claim 6 in which glycinetransport inhibitors are used in place of glycine agonists at dosessufficient to augment NMDAR-mediated neurotransmission.
 15. The methodof claim 14 in which the glycine transport inhibitors inhibit transportat GLYT1- or GLYT2-type glycine transporters.
 16. The method of claim 14in which the glycine transport inhibitors inhibit transport at System A,System L, System ASC, System N.
 17. The method of claim 6 in which Damino acid oxidase inhibitors are used in place of glycine-site agonistsat doses sufficient to augment NMDAR-mediated neurotransmission.
 18. Themethod of claim 6 in which serine hydroxymethyltransferase or serineracemase modulators are used in place of glycine-site agonists at dosessufficient to augment NMDAR-mediated neurotransmission.
 19. The methodof claim 6 in which glycine is used at a dose of between 15 and 150 gper day.
 20. The method of claim 6 in which d-serine is used at a doseof 250 mg-20 g per day.
 21. The method of claim 6 in which d-cycloserineis used at a dose of 25 mg-1000 mg per day.
 22. The method of claim 6 inwhich NMDAR agonists are added to other medications known to beeffective in treatment of movement disorders, selected from the groupconsisting of L-dopa and other dopaminergic agents, anticholinergics,adenosine modulators, NMDA antagonists and combinations thereof.
 23. Themethod of claim 6 in which the movement disorder is the result oftreatment with antipsychotic medication.
 24. The method of claim 23 inwhich the movement disorder is drug-induced Parkinsonism, akathasia, ortardive dyskinesia.
 25. The method of claim 6 where the movementdisorder is the result of neurological illness.
 26. The method of claim25 where the movement disorder is Parkinsons disease, Huntingtonschorea, Wilsons disease, Tourette's disease, tic disorders, orobsessive-compulsive disorder.
 27. A pharmaceutical composition for thetreatment of a movement disorder comprising a prodrug of an NMDARagonist or precursor thereof as active ingredient therein in combinationwith a pharmaceutically acceptable carrier.
 28. A method for thetreatment of a movement disorder comprising administering to a patient atherapeutically effective amount, for alleviating motor disordersymptoms, of a prodrug of an NMDAR agonist or precursor thereof.